Prophylactic Use of Vitamin E for Prevention of Occupational PAH-Induced Damage

预防性使用维生素 E 预防职业性 PAH 引起的损害

• 批准号: 7660490
• 负责人: DEBBIE MUSTACICH
• 金额: $ 18.28万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-18 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7660490
• 关键词: ABCB1 gene; ATP-Binding Cassette Transporters; Acute; Air; Antioxidants; Applications Grants; Aromatic Polycyclic Hydrocarbons; Automobile Exhaust; Benzo(a)pyrene; Bile fluid; Biliary; Biological Markers; Breathing; Burn injury; Cigarette Smoker; Coal; Coke; Complex Mixtures; DNA Adduction; DNA Adducts; DNA Damage; Data; Development; Disasters; Disease susceptibility; Dose; Drug Formulations; Drug Metabolic Detoxication; Environmental Pollutants; Environmental Tobacco Smoke; Enzymes; Excretory function; Exposure to; F2-Isoprostanes; Fire - disasters; Future; Goals; Hazardous Waste Sites; Health; Hepatic; Human; Individual; Kidney; Knowledge; Leukocytes; Life; Liver; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Metabolism; Modeling; Multidrug Resistance Gene; National Institute of Environmental Health Sciences; Occupational; Occupational Exposure; Operative Surgical Procedures; Organ; Oxidative Stress; Pathology; Pathway interactions; Phase; Plants; Plasma; Play; Polycyclic Compounds; Prevention; Proteins; Public Health; Qualifying; Rattus; Recommendation; Regulation; Role; Route; Site; Suggestion; Supplementation; Tissues; Tocopherols; Tocotrienols; Toxic Environmental Substances; Toxic effect; Treatment Protocols; Urine; Vitamin E; Work; Xenobiotic Metabolism; Xenobiotics; adduct; base; cigarette smoking; evidence base; forest; high risk; improved; innovation; liver function; nutrition; oxidative DNA damage; prevent; prophylactic; protective effect; protein expression; public health relevance; response; superfund site; urinary

DESCRIPTION (provided by applicant): Polycyclic aromatic hydrocarbons (PAHs), including benzo(a)pyrene (BP), form a major class of environmental pollutants suggested to be causative factors in a variety of disease susceptibilities, including cancer. Virtually all PAH mixtures contain BP; a model compound that causes the formation of BP-DNA-adducts. Levels of BP-DNA adducts in cigarette smokers are decreased by vitamin E (a-tocopherol) administration. Although a-tocopherol's antioxidant activity has been the proposed mechanism for its protective effects, our recent provocative findings indicate that a-tocopherol also has a regulatory function in liver. Thus, a-tocopherol's action in eliminating BP-induced DNA damage likely involves regulation of hepatic detoxification and biliary excretion. There is, therefore, a need to evaluate a-tocopherol-dependent modulation of hepatic xenobiotic metabolism and disposition as mechanisms for the detoxification and elimination of PAHs. Our long-range goal is to determine the efficacy of prophylactic high dose vitamin E supplementation for prevention of DNA-adduct formation during occupational exposure to PAHs. Our objective in this R21 application is to identify the key mechanism(s) by which a-tocopherol supplementation alters the response of hepatic, lung and kidney tissues to PAHs utilizing BP as a model compound. Our central hypothesis is that pharmacologic a-tocopherol supplementation, in addition to providing increased antioxidant protection, increases xenobiotic metabolism and excretion pathways, thereby protecting the liver and other organs from PAH-induced DNA adduct formation by increasing detoxification and/or elimination of PAHs and their metabolites from the body. We propose to: Aim 1. Determine modulation of BP metabolism and excretion by a-tocopherol in rats. Our working hypothesis is that elevated levels of a-tocopherol will significantly increase: (1) metabolism of BP to non-DNA reactive metabolites and (2) increase BP and/or BP metabolite excretion. Aim 2. Identify the protective effects of a-tocopherol supplementation against BP-induced DNA damage. Our working hypothesis is that elevated levels of a-tocopherol will decrease BP-induced DNA damage in liver, lung and kidney by two synergistic mechanisms: (1) increased antioxidant protection against oxidative stress- induced damage and (2) decreased formation of covalent BP-DNA adducts. This proposal is innovative because it challenges the current paradigm that -tocopherol acts almost exclusively as an antioxidant, while supporting the paradigm that nutrition and dietary regiments can modulate toxicological insults and resultant pathologies. The public health relevance of these studies is that evidence that pathways other than antioxidant activity are functionally operative in a-tocopherol-mediated protection against environmental pollutants such as PAHs would be of considerable value in the ultimate development of protective strategies for acute occupational exposures to these and other environmental pollutants. Benzo(a)pyrene, a polycyclic aromatic hydrocarbon, has been found at more National Priority List hazardous waste sites than any other polycyclic aromatic hydrocarbon. DNA damage due to benzo(a)pyrene exposure has been correlated with lung cancer occurrence in workers exposed occupationally to this carcinogenic compound. The ubiquitous environmental and occupational presence and the negative association between human health and exposure to benzo(a)pyrene, adds urgency to the need to fill in the gaps in our knowledge of the mechanisms by which high-risk workers, as well as people living near toxic spills, disaster sites and Superfund sites, may be protected from the deleterious effects of benzo(a)pyrene exposure. PUBLIC HEALTH RELEVANCE: Benzo(a)pyrene, a polycyclic aromatic hydrocarbon, has been found at more National Priority List hazardous waste sites than any other polycyclic aromatic hydrocarbon. DNA damage due to benzo(a)pyrene exposure has been correlated with lung cancer occurrence in workers exposed occupationally to this carcinogenic compound. The ubiquitous environmental and occupational presence and the negative association between human health and exposure to benzo(a)pyrene, adds urgency to the need to fill in the gaps in our knowledge of the mechanisms by which high-risk workers, as well as people living near toxic spills, disaster sites and Superfund sites, may be protected from the deleterious effects of benzo(a)pyrene exposure.

描述（由申请人提供）：多环芳烃（PAH），包括苯并（a）芘（BP），是一类主要的环境污染物，被认为是多种疾病易感性的致病因素，包括癌症。几乎所有 PAH 混合物都含有 BP；导致 BP-DNA 加合物形成的模型化合物。服用维生素 E（α-生育酚）可降低吸烟者体内 BP-DNA 加合物的水平。尽管α-生育酚的抗氧化活性已被认为是其保护作用的机制，但我们最近的令人兴奋的发现表明α-生育酚在肝脏中也具有调节功能。因此，α-生育酚消除 BP 引起的 DNA 损伤的作用可能涉及肝脏解毒和胆汁排泄的调节。因此，需要评估α-生育酚依赖性的肝脏异生物质代谢和处置调节，作为多环芳烃解毒和消除的机制。我们的长期目标是确定预防性高剂量维生素 E 补充剂对于预防职业接触 PAH 期间 DNA 加合物形成的功效。我们在此 R21 应用中的目标是利用 BP 作为模型化合物，确定补充 α-生育酚改变肝、肺和肾组织对 PAH 反应的关键机制。我们的中心假设是，药理α-生育酚补充剂除了提供增强的抗氧化保护之外，还增强外源代谢和排泄途径，从而通过增强体内多环芳烃及其代谢物的解毒和/或消除，保护肝脏和其他器官免受多环芳烃诱导的DNA加合物形成。我们建议： 目标 1. 确定α-生育酚对大鼠血压代谢和排泄的调节作用。我们的工作假设是，α-生育酚水平升高将显着增加：(1) BP 代谢为非 DNA 反应性代谢物，(2) 增加 BP 和/或 BP 代谢物排泄。目标 2. 确定补充 α-生育酚对 BP 引起的 DNA 损伤的保护作用。我们的工作假设是，α-生育酚水平升高将通过两种协同机制减少 BP 诱导的肝、肺和肾 DNA 损伤：(1) 增强抗氧化保护，防止氧化应激诱导的损伤；(2) 减少共价 BP-DNA 加合物的形成。该提案具有创新性，因为它挑战了当前生育酚几乎完全充当抗氧化剂的范式，同时支持营养和饮食疗法可以调节毒理学损伤和由此产生的病理学的范式。这些研究与公共卫生的相关性在于，证明抗氧化活性以外的途径在α-生育酚介导的针对多环芳烃等环境污染物的保护中发挥功能性作用的证据，对于最终制定针对急性职业暴露于这些和其他环境污染物的保护策略具有相当大的价值。苯并(a)芘是一种多环芳烃，在国家优先名单中发现的危险废物场比任何其他多环芳烃都多。苯并(a)芘暴露造成的 DNA 损伤与职业接触这种致癌化合物的工人的肺癌发生有关。无处不在的环境和职业存在以及人类健康与接触苯并（a）芘之间的负相关性，增加了我们迫切需要填补我们对高风险工人以及居住在有毒泄漏、灾难现场和超级基金地点附近的人们免受苯并（a）芘接触有害影响的机制的了解的空白。公共健康相关性：苯并(a)芘是一种多环芳烃，在国家优先名单中发现的危险废物场比任何其他多环芳烃都多。苯并(a)芘暴露造成的 DNA 损伤与职业接触这种致癌化合物的工人的肺癌发生有关。无处不在的环境和职业存在以及人类健康与接触苯并（a）芘之间的负相关性，增加了我们迫切需要填补我们对高风险工人以及居住在有毒泄漏、灾难现场和超级基金地点附近的人们免受苯并（a）芘接触有害影响的机制的了解的空白。